Ductal pancreatic adenocarcinoma is one of the five largest cancer killers in adults. The failure of current therapeutic strategies in patients with this malignancy suggests that a better understanding of the integrative pathophysiology of neoplastic pancreatic duct cells will be required to develop effective novel strategies. Based on the importance of certain G protein-coupled receptors to duct cell physiology, we feel that their second messengers may play key growth modulatory roles. PRELIMINARY STUDIES in our laboratory support the UNIFYING HYPOTHESIS that VIP-1 receptors are commonly expressed in human ductal pancreatic adenocarcinomas and couple to opposing pathways with the potential to both stimulate and arrest tumor growth. Specifically, our data suggest that VIP-1 receptors couple to both cAMP-independent growth stimulatory and cAMP-dependent growth inhibitory pathways in neoplastic pancreatic duct cells. With regard to the later, cAMP inhibits tyrosine kinase receptor (TKR)-induction of mitogen-activated protein kinases, TKR-stimulated G1 yields S phase transition, and subsequent progression of neoplastcic pancreatic duct cells through G2/M. Based on the potential importance of these findings, we will further test this UNIFYING HYPOTHESIS through studies (1) comparing the effects of VIP and forskolin ( a direct activator of adenylyl cyclases ) on in vitro growth of a variety of VIP-1 receptor-bearing human tumor- derived cell lines with well-defined molecular profiles , (2) confirming the identity of growth stimulatory and growth inhibitory pathways activated by VIP-1 receptors in these cells, and (3) defining the mechanisms through which cAMP inhibits G1 yields S phase transititon and subsequent progression of these cells through G2/M. VIP's modest overall effect on in vitro growth of VIP-1 receptor-bearing human tumor- derived cells, presumably reflecting concomitant activation of growth stimulatory and growth inhibitory pathways, suggests that generic VIP receptor antagonists will not provide us with a magic bullet . Rather, in order to achieve our GOAL - to eventually turn this widely expressed adenylyl cyclase-coupled receptor to our advantage in combination therapeutic strategies-we must first discern the specific growth regulatory roles of its G protein-coupled second messengers in human ductal pancreatic cancers.